During embryonic development, the formation of primary vascular networks occurs by vasculogenesis -- the in situ differentiation of progenitor cells to endothelial cells that organize into a primitive network. The subsequent remodeling of the vasculogenic network into a functionally efficient vasculature occurs through angiogenesis -- the sprouting of new capillaries from a preexisting network. We have introduced the term "vasculogenic mimicry" to describe the unique ability of aggressive melanoma tumor cells to form tubular structures and patterned networks in 3-D culture, which "mimics" the pattern of embryonic vasculogenic networks and recapitulates the patterned networks seen in patients' aggressive tumors -- correlating with poor prognosis. The molecular profile of these aggressive tumor cells suggests that they have a deregulated genotype, capable of expressing an endothelial-like phenotype. Our preliminary studies indicate that: 1) aggressive melanoma cells express VE-cadherin (exclusively expressed by endothelial cells); 2) aggressive tumor cells produce an extracellular matrix (ECM) that induces poorly aggressive melanoma cells to form vasculogenic networks; and 3) aggressive melanoma cells participate in the revascularization of an ischemic limb model, thus illustrating their endothelial stem cell plasticity. The proposed studies advance observations made during the current funding period regarding the embryonic-like phenotype of aggressive melanoma cells: Aim 1: Determine the functional significance of VE-cadherin expression in human melanoma tumor cells engaged in endothelial transdifferentiation and vasculogenic mimicry. Aim 2: Identify the key molecular components produced by aggressive melanoma tumor cells that induce poorly aggressive melanoma cells to form vasculogenic networks and mimic endothelial cells. Aim 3: Investigate the stem cell plasticity of aggressive melanoma tumor cells for their potential to re-vascularize tissues in animal models of wound healing and ischemia. The data generated from these novel studies will provide new molecular markers for clinical diagnosis and new concepts regarding the trarisendothelial differentiation of aggressive melanoma tumor cells and their stem cell plasticity.